Many diseases and conditions result from neuropathy, including, for example, amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease), Parkinson's disease, retinal degeneration, Charcot-Marie-Tooth (CMT) disease, neuropathic pain and chemotherapy-induced neuropathies. Moreover, neuropathy (e.g., neuropathic pain) can result from trauma to neural tissue, such as nerve crush and spinal cord injuries. Therapies that stimulate neural regeneration would be advantageous for the treatment of these conditions.
For example, diabetic neuropathies are a family of nerve disorders caused by diabetes. People with diabetes can, over time, experience damage to nerves throughout the body. Neuropathies lead to numbness and sometimes pain and weakness in the hands, arms, feet, and legs. These neurological problems may also occur in every organ system, including the digestive tract, heart, and sex organs. People with diabetes can develop nerve problems at any time, but the longer a person has diabetes, the greater the risk. In Parkinson's Disease (PD), patients experience a loss of dopamine-secreting neurons in the substantia nigra. PD patients suffer from tremors, limb rigidity, akinesia and bradykinesia as well as a failure of postural reflexes which can lead to instability and falls. Diseases associated with retinal degeneration include diabetic retinopathy, retinitis pigmentosa and age-related macular degeneration (AMD). These diseases can lead to vision loss, and AMD is the leading cause of adult legal-blindness in the United States.
The treatment options for neural degenerative conditions are currently limited. For example, diabetic neuropathies are currently treated primarily by controlling the diabetic condition per se. U.S. Patent Publication No. 20050267061 describes a treatment of neuropathies using zinc finger transcription factors that modulate VEGF-A expression. U.S. Pat. No. 7,253,273 disclose zinc finger proteins targeted to Nav1.8, TrkA and VR1 for treatment of neuropathic pain. Treatment for PD is tied to symptom management. The most widely used form of treatment is L-Dopa, but over time, use of exogenous L-Dopa causes a decrease in endogenous L-Dopa production, and eventually becomes counter productive.
Several groups have also reported that administration of neurotrophic molecules per se may help ameliorate nerve degeneration. For example, Schratzberger et al. (2001) J. Clin. Inv. 107, 1083-1092, demonstrated that gene transfer of vascular endothelial growth factor (VEGF) could reverse diabetic neuropathy characterized by a loss of axons and demyelination in the rat experimental model. In addition, see, Isner et al. (2001) Hum Gene Ther. 10; 12(12):1593-4; Sondell et al. (2000) European J. Neurosciences 12:4243-4254; Sondell (1999) J. Neurosciences 19(14):5731-5740.
The neurotropic factor, NT-3, has been shown to function in promoting the survival, growth and differentiation of neurons, whereas NT-3 deficiency results in an impairment in the peripheral nervous system. NT-3 deficiency is also linked to neuropathy in experimental diabetic rats. Although gene transfer of NT-3 cDNA has shown preclinical efficacy against neuropathy in a various neuropathy animal models, the NT-3 based therapy has not been used in the clinic because of the potential problems associated with the use of NT-3 cDNA or recombinant NT-3 proteins. The direct use of NT-3 recombinant protein is limited by its short half-life, poor bioavailability and dose-limiting toxicities. See, Pradat et al. (2001) Hum. Gene Ther. 12:2237-2249; Young et al. (2001) Restor Neurol. Neurosci. 18:167-175; Mata et al. (2006) Expert Opin Biol. Ther. 6:499-507. In addition, gene transfer of NT-3 cDNA may lead to the over-production of NT-3 protein, resulting in unwanted toxicities.
Another neurotrophic factor that has been shown to be a potent survival factor for many different types of neuronal cells, such as dopaminergic neurons, striatal neurons, motor neurons and photoreceptor cells is glial cell line-derived neurotrophic factor (GDNF). See, e.g., Airaksinen et al. (2002) Nature Rev Neurosci. 3:384-394. However, no overall symptomatic improvement was observed in Phase 2 studies of Parkinson's patients receiving infusions of recombinant glial cell line-derived neurotrophic factor (GDNF). See, e.g., Lang (2006) Ann Neurol 59:459-466. Furthermore, Lang et al. reported that recombinant GDNF infusion resulted in significant side effects (e.g. generation of neutralizing antibodies reactive against both recombinant and endogenous GDNF), likely caused by imprecise delivery of the high doses of the recombinant protein.
Thus, there remains a need for compositions and methods for the treatment of neuropathies such as diabetic neuropathy, neuropathic pain, and various neurodegenerative conditions characterized by the loss or death of neurons or the failure of damaged neurons to regenerate.